Proteostasis or protein homeostasis is a cellular network essential for the strict control of protein synthesis, protein folding, maintenance of conformation, and protein degradation. Depending on the proteomic demands, the expression of the proteostasis network (PN) differs in cells and tissues.

Proteostasis Network

The different machineries that are part of the PN are translational machinery, molecular chaperones, co-chaperones, ubiquitin-proteasome system, as well as autophagy (lysosome) machinery. In addition, stress response pathways such as heat shock response (HSR) pathways and unfolded protein response (UPR) pathways are important PN modifiers. Auxiliary factors that are required for proteostasis are signaling pathways, metabolic factors, chromatin remodelers, transcription, and post-translational modification regulators.

Exposure to environmental irritants or stress, aging, or alteration of physiology are some factors that can alter the activity of PN. Loss or alteration of proteostasis can lead to the aggregation of nonnative proteins paving way for a host of diseases such as metabolic disorders, cardiac disease, neurodegeneration, mechanical injury, and cancer.

Effect of Protein Aggregation on the Proteostasis Pathways

Loss of proteostasis leads to protein aggregation that is responsible for dysregulation of the chaperone and co-chaperone levels. Studies have demonstrated that dysregulation of chaperones reduces the levels of soluble heat shock proteins (Hsp) such as Hsp 70, Hsp 90, and Hsp40 in mouse and nematode models of Alzheimer’s disease (AD). In addition, the aggregated proteins undergo ubiquitination that then accumulate in the brain tissue to cause inhibition of proteasome and neurotoxicity. The autophagic pathways are also inhibited by protein aggregation.

Apart from the disruptions caused to the different machineries of PN, cell culture studies show that these aggregated proteins have a tendency to spread. However, despite protein aggregation and spreading being a common feature in neurodegenerative diseases, the mechanism of internalization and transmission is extremely specific to each disease.

Diseases and Their Link to Proteostasis

Defects or alteration in the proteostasis pathways are linked to a number of diseases.

Neurodegenerative diseases

The hallmark of neurodegenerative disease is protein aggregation. These aggregates are usually seen as detergent-insoluble inclusions in the nucleus and cytoplasm of the neurons. Although ATF6 and IRE1α are required for control of protein folding and degradation, they do play a role in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and AD. Post-mortem studies on human spinal cord from ALS cases and on the frontal and temporal cortex of AD cases reveal that the IRE1-XBP1 (X-box binding protein 1) and ATF6 target genes are activated in ALS and AD. This indicates that these target genes also have disease-specific patterns that can activate differential gene sets.

Cardiac diseases

Derailed proteostasis is also leads to various cardiac malfunctions. Cardiomyocytes are highly specialized proteins that require critical protein quality surveillance for their optimal function. These muscles also have a high metabolic demand because of which there is production of substantial amounts of proteotoxic agents, especially reactive oxygen species. In the event of absence of proteostasis, toxic, misfolded, and amyloid-like protein aggregates start accumulating. Aberration in the proteostasis function can also cause genetic mutations leading to cardiac diseases.

Cognitive impairment

Neutral sphingomyelinase phosphodiestrase-3 (SMPD3) is a stress-regulated gene found in the neurons of the brain. Studies conducted on mouse brain suggest that the absence of SMPD3 in the Golgi compartment of the brain neuron is linked to cognitive impairment. Proteostasis and lipid bilayer remodeling are affected when SMPD activity does not take place.

Hereditary skeletal disorders

Mutations in the type 1 procollagen genes gives rise to rare bone disorders. Studies have revealed that disruption in the proteostasis pathway is one of the many reasons for these disorders.

Rhodopsin retinitis pigmentosa

Mutations in rhodopsin, a rod visual pigment, is responsible for retinitis pigmentosa. This degenerative condition finally leaves the individual blind. In-depth characterization of the rhodopsin mutations have shown that the mutations can be divided into seven classes. Some of these mutations have been attributed to defects in protein folding and proteostasis disruption.

Inherited diseases, such as cystic fibrosis, cockyane syndrom are also caused due to defects in the multiple proteostasis pathways.

Introduction of high-throughput omics technologies in this field in combination with the study of structural and cross-link biochemistry can provide a novel approach to understand the differences in the mechanism of proteostasis in a healthy and diseased body. This data can be used to develop targeted gene therapy.